Our ability to move and breathe depends upon the neuromuscular synapse. As such, the neuromuscular synapse is the single synapse essential for survival. Neuromuscular synapse formation is a multi-step process requiring coordinated interactions between motor neurons and muscle fibers, which eventually lead to the formation of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal. As a consequence, acetylcholine receptors (AChRs) become highly concentrated in the postsynaptic membrane and arranged in perfect register with active zones in the presynaptic nerve terminal, and thus ensure fast, robust and reliable synaptic transmission. The signals and mechanisms responsible for this process are poorly understood but require MuSK, a receptor tyrosine kinase that is expressed in skeletal muscle, Agrin, a motor neuron-derived ligand that stimulates MuSK phosphorylation, and Lrp4, the receptor for Agrin. These genes play critical roles in synaptic differentiation, as synapses do not form in their absence, and mutations in MuSK or downstream effectors lead to a reduced number of AChRs at synapses and are a major cause of a group of neuromuscular disorders, termed congenital myasthenia. Moreover, auto-antibodies to AChRs, MuSK or Lrp4, which cause accelerated degradation of AChRs and structural disorganization of the synapse, are responsible for myasthenia gravis.
The mechanisms that control and stabilize connections between motor axon terminals and muscle fibers are poorly understood, but the maintenance of neuromuscular synapses is essential to sustain synaptic transmission and prevent muscle atrophy. In amyotrophic lateral sclerosis (ALS), a loss of motor axon terminals, which causes muscle denervation, is the earliest known sign of disease. ALS is a devastating, neurodegenerative disorder, with a midlife onset, characterized by the progressive loss of upper and lower motor neurons and leading to relentless, lethal paralysis. Following diagnosis of ALS, either sporadic or familial, the time course of disease progression varies in an unpredictable manner. Dominant mutations in superoxide dismutase (SOD1) are responsible for 2% of the cases of ALS. Transgenic mice expressing mutant forms of SOD1 develop a paralytic motor neuron disease, which exhibits all of the hallmark features of ALS.
A progressive and gradual withdrawal of motor axon terminals accompanies aging, compromising synaptic function and causing muscle atrophy, or sarcopenia. Once this cycle is initiated, muscle atrophy and deterioration are further exacerbated, as muscle atrophy and a loss of muscle strength reduce physical activity and exercise, which decreases synaptic activity still further. Sarcopenia is a major and debilitating consequence of aging. Moreover, because sarcopenia reduces physical activity, sarcopenia compromises health by contributing to a wide range of complications in multiple organ systems.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.